PROJECT SUMMARY Adoptive cell transfer (ACT) therapies for cancer patients have failed to fulfill their therapeutic promise, due to the transfer of short-lived and terminally differentiated cells. A lack of means for developing durable T cell potency has hampered ACT advancement in the clinic. Understanding and manipulating the pathways that sustain T cell memory will potentially unlock durable responses to tumors. We recent found that IL-17A/IFN- ?/IL-22-producing CD4+ T cells that express enzymatically active CD26 on their cell surface?termed human CD26hiCD4+ T cells?demonstrate exquisite responses to tumors compared to Th1, Th2 or Th17 cells. Further investigation revealed that these cells potently induce the expansion and engraftment of cytotoxic CD8+ T cells in vivo. Interestingly, we found that abrogating the enzymatic activity of CD26 on CD26hiCD4+ but not on CD8+ or CD26negCD4+ T cells with Alogliptin impaired their capacity to secrete IFN-?. Collectively, our data suggest that CD26 plays a role in the cytotoxicity of CD26hiCD4+ T cells and could augment CD8+ T cell engraftment in vivo, in turn mediated curative responses in mice with murine and human tumors. The importance of CD26 on CD26hiCD4+ T cell function, metabolism and cytotoxicity will be investigated using various tools to pharmaceutically or genetically manipulate CD26 enzyme activity. Based on our new findings, the loss of function, metabolism and memory induced by the inhibition of CD26 enzymatic activity could potentially reduce the ability of CD26hiCD4+ T cells to support CD8+ T cells. It is important to deduce how CD26 on CD26hiCD4+ T cells cancer immunotherapy and if this activity and co-signaling molecules can be targeted for enhance therapy against this aggressive pancreatic cancer. We propose to gain further insight into CD26hiCD4+ T cell-mediated tumor immunity, hypothesizing that CD26 plays a crucial role in the anti-tumor activity of human CD26hiCD4+ T cells as well as their ability to support CD8+ T cells (Aim 1), and that these cells have unique self-renewing properties that prolong their efficacy of cancer immunotherapy after multiple rounds of serial transfer (Aim 2). We will also target co-stimulatory molecules on these cells to enhance their capacity to kill human pancreatic cancer (Aim 3). Our proposed research is expected to demonstrate that manipulation of the CD26 pathway may induce durable immunity against the growth and recurrence of advanced malignancies.